1. Field of the Invention
This invention is in the field of medical diagnostics and therapy. In particular, the invention relates to methods for diagnosing Alzheimer's Disease (AD) by determining the level or function of insulin, insulin-like growth factors, their receptors and/or their downstream signaling molecules. The invention further relates to methods for the treatment of AD by administering an insulin agonist and an insulin-like growth factor agonist. The invention additionally provides an animal model of AD and methods of screening for agents useful in the treatment, amelioration, or prevention of AD.
2. Related Art
The characteristic neuropathological and molecular lesions that correlate with dementia in Alzheimer's Disease (AD) include the accumulation of hyper-phosphorylated and poly-ubiquinated microtubule-associated proteins, such as tau, resulting in the formation of neurofibrillary tangles, dystrophic neuritis, and neuropil threads. Neuronal cytoskeletal abnormalities are associated with cerebral atrophy with cell and fiber loss, and synaptic disconnection. Increased amyloid-beta (Aβ) deposition around and within the walls of meningeal and cortical vessels, the cortical neuropil, and neuronal perikarya is a feature of both AD and normal aging. Although genetic factors can predispose individuals to develop premature and excessive cerebral deposits of Aβ in AD-type dementia, most cases are sporadic and do not exhibit clear familial or genetic clustering. Recent exploration of biochemical, molecular, and cellular abnormalities that precede or accompany classic AD demonstrated that cell loss was associated with increased activation of pro-death genes and signaling pathways, impaired energy metabolism, mitochondrial dysfunction, chronic oxidative stress, and cerebrovascular disease/cerebral hypoperfusion. However, the inability to interlink these phenomena under a single primary pathogenic mechanism resulted in the emergence and propagation of various heavily debated theories, each of which focused on how one particular component of AD could trigger a cascade that contributes to the development of all other known abnormalities. However, re-evaluation of some of the older literature revealed that impairment in cerebral glucose utilization and energy metabolism represent very early abnormalities that precede or accompany the initial stages of cognitive impairment. Additionally, there is emerging evidence that impaired insulin signaling may have an important role in the pathogenesis of AD.
Currently, there is a growing interest in clarifying the roles of insulin resistance, hyperinsulinemia, Type 2 Diabetes Mellitus, and insulin degrading enzyme in the pathogenesis of AD, and its associated neuronal cytoskeletal lesions and Aβ deposits in the brain. This relatively new wave of enthusiasm is fueled by reports showing reduced brain growth and increased tau phosphorylation in mice deficient in either the insulin receptor substrate-2 or the neuronal insulin receptor gene. (Schubert et al., J. Neurosci. 23:7084 (2003); Schubert et al., Proc. Natl. Acad. Sci. USA 101:3100 (2004)). The potential role of the neuroendocrine system in AD was raised 15 to 20 years ago when abnormalities in the hypothalamic-pituitary axis were detected. (Beal et al., Res. Publ. Assoc. Res. Nerv. Ment. Dis. 64:215 (1986); Reubi et al., J. Neurol. 233:370 (1986); Fisman et al., J. Am. Geriatr. Soc. 36:298 (1988); Hoyer, J. Neurol. 234:266 (1987); Tham et al., Acta Psychiatr. Scand. 77:719 (1988); Bucht et al., Acta Med. Scand. 213:387 (1983)). That concept nearly vanished with the tidal wave of accelerated research on Aβ and tau, although presently, the renewed interest in neuroendocrine mechanisms emphasizes systemic disease rather than intrinsic central nervous system (CNS) endocrine dysfunction. However, previous research revealed that many important components of CNS neurodegeneration that occur in AD are mediated by impaired insulin signaling in the brain. (de la Monte et al., Cell. Mol. Life Sci. 58:1950 (2001); de la Monte et al., Cell. Mol. Life Sci. 59:882 (2002); de la Monte et al., Alcohol Clin. Exp. Res. 24:716 (2000); Xu et al., J. Biol. Chem. 278:26929 (2003)).